Method for the purification of liponic acid

ABSTRACT

The invention relates to a process for purifying lipoic acid, which comprises adding to a solution of lipoic acid at least 0.1 times the amount of an adsorbent, based on the mass of lipoic acid to be purified, and subsequently removing the adsorbent. It is possible in this way to provide racemic or nonracemic lipoic acid with an oligomer content below 1% by weight, for example from 0.1 to 1% by weight.

The present invention relates to a process for purifying racemic ornonracemic lipoic acid. In particular, the invention relates to aprocess for purifying R- or S-lipoic acid which has an oligomer contentin the range from about 0.1 to about 1.0% by weight.

The invention further relates to the use of the lipoic acid purified inthe manner according to the invention in drugs, cosmetics and foodproducts.

Dihydrolipoic acid and lipoic acid are naturally occurring substanceshaving particular importance in cellular metabolism. R-Lipoic acid playsa central part in energy generation as coenzyme, e.g. pyruvatedehydrogenase. R-Lipoic acid is activated, in order to display fully itsvery good antioxidant properties, to dihydrolipoic acid in metabolism.Dihydrolipoic acid and lipoic acid can, because they are interconvertedin vivo, be used for the same areas of application. R-Lipoic acid has anadvantageous effect on age-related changes in metabolism and istherefore also of interest in the cosmetic sector.

Lipoic acid and dihydrolipoic acid can be employed as nutraceuticals inthe food product sector. The use of dihydrolipoic acid and/or lipoicacid as drug is also possible. For example, it is known that R-lipoicacid increases insulin sensitivity and thus can be used as antidiabetic,and for preventing and alleviating late damage from diabetes. Inaddition, lipoic acid or dihydrolipoic acid or derivatives thereof canbe employed for the treatment of disorders of glucose metabolism (e.g.in the CNS), for insulin resistance, cancer and hearing defects.

Numerous methods for preparing optically pure R- and S-lipoic acid anddihydrolipoic acid are known from the literature (G. Bringmann, D.Herzberg, G. Adam, F. Balkenhohl, J. Paust, Z. Naturforschung 1999, 54b,665-661; B. Adger et al., Bioorg. Med. Chem. 1997, 5, 253-61; J. S.Yadav, S. Mysorekar, K. Garyali, J. Scientific & Industrial Res. 1990,49, 400409; A. S. Gopalan, H. K. Jacobs, Tetrahedron Lett 1989, 42,5705; M. H. Brookes, B. T. Golding, A. T. Hudson, Perkin Transaction 1,1988, 9-12; M. H. Brookes, B. T. Golding, D. A. Howes, A. T. Hudson,Chemical Communication 1983, 1051-53; JP 1960-35704; EP-A-543088;EP-A-487 986; DE-A-100 44 000 and DE-A-100 59 718).

Since lipoic acid and dihydrolipoic acid are also intended to be used inhumans, products of maximal purity are desired, and simple and economicproduction thereof in large quantities must be ensured.

It is to be regarded as particularly problematic in this connection thatthe lipoic acid obtained is contaminated by characteristic impuritiesresulting from oligomerization or polymerization of lipoic acid itself.Even small quantities of these oligomers in the product lead to seriouscomplications during further processing and cannot be tolerated inrelation to a pharmaceutical use of the lipoic acid produced in thisway.

DE-A-100 44 000 and DE-A-100 59 718 describe a clarifying filtrationprocess for purifying lipoic acid obtained by oxidation of dihydrolipoicacid, which is suitable for experiments on a laboratory scale.

Industrial production of lipoic acid with oligomer contents of less than1.0% by weight by contrast presents a problem which has not yet beensatisfactorily solved.

It is an object of the present invention to develop a process forpurifying lipoic acid which can also be applied economically on theindustrial scale.

We have found that this object is achieved by a process for purifyinglipoic acid, which comprises adding to a solution of lipoic acid atleast 0.1 times the amount of an adsorbent, based on the mass of lipoicacid to be purified, and subsequently removing the adsorbent. It ispossible in this way to provide racemic or nonracemic lipoic acid withan oligomer content of less than 1% by weight, for example from 0.1 to1% by weight.

Solvents suitable for producing solutions for the lipoic acidpurification process of the invention are organic solvents of lowpolarity, especially aliphatic, where appropriate heteroatom-substitutedhydrocarbons having from one to twelve carbon atoms, such as, forexample, pentane, hexane, cyclohexane, heptane or dichloroethane oraromatic, where appropriate alkyl- or heteroatom-substitutedhydrocarbons such as toluene, ethylbenzene or chlorobenzene or mixturesof said solvent classes.

Preferred solvents for the purification process of the invention arealiphatic hydrocarbons having from one to twelve carbon atoms andalkyl-substituted aromatic hydrocarbons having up to twelve carbonatoms.

Particularly preferred solvents are pentane, hexane, cyclohexane,heptane, octane, toluene and ethylbenzene, very particularly preferablyheptane and toluene or mixtures of at least two of said solvents.

Suitable adsorbents are commercially available adsorbents such as silicagels, neutral aluminas, basic aluminas and mixtures of said adsorbents,preferably silica gels.

Particularly preferred adsorbents are silica gel 60 having a particlesize of 0.04-0.063 mm, silica gel 40 (particle size 0.015-0.035 mm) andsilica gel 100 (particle size 0.063-0.2 mm).

The quantity of the adsorbent to be employed in the purification processof the invention depends on the quantity of lipoic acid to be purifiedand is generally at least 10% of the quantity by weight of the lipoicacid to be purified. This applies in particular on the use of theparticularly preferred adsorbent silica gel. It is particularlypreferred in this connection to use at least 15% by weight silica gelbased on the quantity of lipoic acid to be purified. It is veryparticularly preferred to use from 20 to 50% by weight silica gel basedon the quantity of lipoic acid to be purified.

Separation processes suitable for removing the adsorbent are all thosewhich appear suitable to the skilled worker. It is particularly suitableto carry out a filtration to remove the silica gel which is particularlypreferably employed as adsorbent.

The process of the invention is suitable for purifying racemic andnonracemic lipoic acid. Nonracemic lipoic acid means in this connectionall mixtures of R- and S-lipoic acid in which the two enantiomers arenot present in equal parts.

However, the process of the invention is preferably used to purify R- orS-lipoic acid having an enantiomeric excess (ee) of in each case above80% ee, particularly preferably above 90% ee, very particularlypreferably above 95% ee. It is most preferred to purify R- or S-lipoicacid having an enantiomeric excess of in each case above 99% ee. Thepurification process of the invention is suitable for producingchemically pure R- and S-lipoic acid. It is particularly suitable forproducing R- or S-lipoic acid having a chemical purity of at least 99%,very especially at least 99.5%. It is particularly suitable forproducing R- or S-lipoic acid having a maximum content of 0.5% by weightof the lipoic acid oligomers which are problematic as impurities. Thepurification process of the invention is very particularly suitable forproducing R- or S-lipoic acid having an oligomer content not exceeding0.2% by weight.

The lipoic acid to be purified can be prepurified or be employed assolid or partially dissolved crude product of a preceding process stepin the purification process of the invention. The purification processcan be carried out on any scale. It is particularly suitable, however,for purifying lipoic acid on the industrial scale.

In addition to the process for purifying lipoic acid, the invention alsorelates to the further processing of the R- or S-lipoic acid purifiedaccording to the invention, e.g. into pharmacologically acceptable saltssuch as alkali metal and alkaline earth metal salts or, for example, thetrometamol salt (International nonproprietory name fortris(hydroxymethyl)aminomethane) of R-lipoic acid.

The invention additionally relates also to the use of racemic andnonracemic or enantiopure lipoic acid purified by the process of theinvention in drugs or in cosmetics or in food products, for example asnutraceutical. This includes the formulation of racemic or nonracemiclipoic acid purified in the manner of the invention, especially of R- orS-lipoic acid purified according to the invention in a pharmacologicallyor dermatologically acceptable form.

In relation to the diverse possibilities for formulating and usinglipoic acid, reference may be made by way of example to the contents ofDE-A-100 22 856 and of DE-A-100 27 875 (PCT/EP/01/06385).

The following examples serve to illustrate the invention without,however, restricting it:

Exemplary Embodiment

25.3 kg (250 mol) of triethylamine and 20 kg (100 mol) of methyl(6S)-6,8-dihydroxyoctanoate were introduced into 300 liters of tolueneand, while cooling, 28.6 kg (250 mol) of methanesulfonyl chloride weremetered in. After removal of the triethylammonium hydrochloride, most ofthe solvent was distilled out.

A methanolic solution of 50.7 kg of sodium sulfide and 14.4 kg of sulfurwas then added. After the reaction was complete, the mixture was dilutedwith water, and 40 kg of a 12% strength solution of NaBH₄ in 14 M NaOH(Borol solution) were added. Part of the solvent mixture was distilledout, and the remaining reaction mixture was adjusted to pH 4 withsulfuric acid and then extracted with toluene. The organic phase wasadjusted to pH 9 and extracted with toluene.

The R-dihydrolipoic acid isolated in this way was taken up in water and,after addition of a catalytic quantity of iron(II) sulfate, aerateduntil reaction was complete. This was followed by acidification (pH 2)with sulfuric acid and extraction with toluene. The toluene solution wasmixed with heptane and forced through a pressure filter packed with 5 kgof silica gel 60 under slightly elevated pressure.

The filtered solution was cooled and the R-lipoic acid whichcrystallized out was isolated by pressure filtration and dried in astream of nitrogen.

R-Lipoic acid (ee>99.9%) was obtained in a yield of 73% of theory basedon methyl (6S)-6,8-dihydroxyoctanoate. The content of lipoic acidoligomers was determined by gel permeation chromatography (column: PLgel, eluent THF) to be 0.3%.

COMPARATIVE EXAMPLE

The abovementioned example was repeated under the same conditions apartfrom the purification step. The toluene solution obtained afteracidification with sulfuric acid was mixed with heptane and forcedthrough a pressure filter packed with 1 kg of silica gel 60 underslightly elevated pressure.

The filtered solution was cooled and the R-lipoic acid whichcrystallized out was isolated by pressure filtration and dried in astream of nitrogen.

R-Lipoic acid (ee>99.9%) was obtained in a yield of 73% of theory basedon methyl (6S)-6,8-dihydroxyoctanoate. The content of lipoic acidoligomers was determined by gel permeation chromatography (column: PLgel, eluent THF) to be 2.5%.

1. A process for purifying lipoic acid, which comprises adding to asolution of lipoic acid at least 0.1 times the amount of an adsorbent,based on the mass of lipoic acid to be purified, and subsequentlyremoving the adsorbent.
 2. The process as claimed in claim 1, whereinthe lipoic acid to be purified has been obtained by oxidation ofdihydrolipoic acid.
 3. The process as claimed in claim 1, wherein atleast 0.2 to 0.5 times the amount of an adsorbent, based on the mass oflipoic acid to be purified, is used.
 4. The process as claimed in claim1, wherein the silica gel is used as adsorbent.
 5. The process asclaimed in claim 1, wherein the lipoic acid to be purified is dissolvedin an organic solvent or in a mixture of at least two organic solvents.6. The process as claimed in claim 1, wherein the lipoic acid isdissolved in heptane or toluene or a mixture of these solvents.
 7. Theprocess as claimed in claim 1, wherein racemic or nonracemic lipoic acidis employed as lipoic acid.
 8. (canceled)
 9. A drug, cosmetic, or foodproduct comprising purified lipoic acid obtained by the process asclaimed in claim 1.